Synthesis of chiral iodo-N,O-acetonide aminal scaffolds via an efficient cascade reaction of amino acid-derived epoxides

Article abstract of DOI:10.1016/j.tetlet.2011.10.049

Novel amino acid-derived iodo-N,O-acetonide aminals were developed as chiral, non-epimerizable scaffolds to facilitate complex molecule synthesis. These scaffolds are readily prepared from commercially available amino acid derivatives in ≤6 steps, contain an orthogonally-protected β-hydroxy amine moiety, and feature a directly reactive alkyl-iodide group for facile substitution chemistry. Further, a novel ring opening/cyclization cascade reaction was developed to prepare these compounds efficiently (59-72%) from readily available epoxide derivatives.

Full text of DOI:10.1016/j.tetlet.2011.10.049

Tetrahedron Letters 52 (2011) 6908–6910
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Tetrahedron Letters
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Synthesis of chiral iodo-N,O-acetonide aminal scaffolds via an efficient
cascade reaction of amino acid-derived epoxides
J. Paige Souder a, Zachary M. Evans a, Joshua A. Driver a, Eric J. Pozzo a, Andrew J. Lampkins a,b,
⇑
a Department of Chemistry & Biochemistry, Samford University, 800 Lakeshore Drive, Birmingham, AL 35229, USA
b McWhorter School of Pharmacy, Samford University, 800 Lakeshore Drive, Birmingham, AL 35229, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel amino acid-derived iodo-N,O-acetonide aminals were developed as chiral, non-epimerizable scaf-
folds to facilitate complex molecule synthesis. These scaffolds are readily prepared from commercially
available amino acid derivatives in 66 steps, contain an orthogonally-protected b-hydroxy amine moiety,
and feature a directly reactive alkyl-iodide group for facile substitution chemistry. Further, a novel ring
opening/cyclization cascade reaction was developed to prepare these compounds efficiently (59–72%)
from readily available epoxide derivatives.
Received 16 September 2011
Revised 8 October 2011
Accepted 10 October 2011
Available online 17 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Nature’s set of biological building blocks (i.e., amino acids, mono-
saccharides, etc.), while diverse, all share common chemical charac-
teristics. Perhaps their most critical, from a synthetic point of view,
are the diverse functionality and innate chirality they possess, which
oftentimes template their assembly and facilitate reactions to occur
via defined stereochemical (i.e., enantio- or diastereoselective)
paths. In this manner, biological systems exploit these chemical
scaffolds to routinely construct molecules of varying size, function,
and structural complexity.
Since amino acids are among the most functionalized, easily
manipulated, and inexpensive members of Nature’s chiral pool,
these biomolecules are ideal for generating customized chiral plat-
forms as synthons for complex molecule construction. Examples of
enantiomerically-pure scaffolds, both bio-inspired1 and completely
synthetic,2 in asymmetric synthesis are plentiful. Yet, we believe a
substantial need for broadly-applicable advanced synthons exists
due to the structural and stereochemical diversity in targets cur-
rently being pursued. Further, the templates in current use are
oftentimes narrow in scope, or are plagued with structural short-
comings that can limit their utility. For example, Garner’s alde-
hyde,1a a widely-utilized serine-based scaffold, contains a lone
asymmetric center that is readily epimerizable when reagents are
used that promote enolization.3
efficiently in a minimum number of steps. Third, it should feature
orthogonal protection/reactivity that facilitates subsequent (often
diastereoselective) reaction chemistry.
As such, we set out to design and efficiently construct chiral
multifunctionalized, orthogonally protected amino acid-based
scaffolds containing isolated groups accessible individually based
upon the reaction conditions. Our initial efforts toward preparing
scaffolds that feature these characteristics began with N-Boc-L-leu-
cine (1). We selected this amino acid substrate since its i-butyl side
chain affords keen solubility in organic solvents, which facilitate
rapid and efficient purification of its various derivatives by stan-
dard silica gel-based chromatography.
Our synthetic routes toward various scaffold molecules are dis-
played in Scheme 1. We initially prepared three distinct scaffold
molecules that met our design criteria (vide supra), compounds 4,
6, and 7a. All three arise from known4 epoxide derived amino acid
3a. This key intermediate is prepared in four straight-forward steps
((1) esterification, (2) ester reduction to the primary alcohol, (3)
alcohol oxidation to the aldehyde (2a), and (4) Corey-Chaykovsky
epoxidation) from commercially available 1. Of note, the epoxida-
tion of 2a occurs diastereoselectively, whereby the desired epoxide
(3a) is favored (by a 7:1 ratio), and easily separated from its epimer
by flash chromatography in our hands, consistent with the results of
Konno and co-workers.4b Treatment of epoxide 3a with TMSCl in
pyridine/dichloromethane5 and an equivalent of KCl gives protected
chlorohydrin 4, albeit in poor (20%) yield. This poor yield, coupled
with the poor reactivity 4 displayed toward nucleophiles in our
hands, prompted us to explore the analogous protected iodohydrin
(6). This compound was made in two steps (from 3a) using PPh3 and
molecular iodine to generate iodohydrin 5, followed by standard
TMS protection. Additionally, we prepared this compound in high
yield in a single step by treating 3a with TMSI (generated in-situ)
Several key characteristics must be present in order for a scaf-
fold molecule, no matter how structurally elegant, to find applica-
tion(s) as a potential platform for complex molecule construction.
First, it should contain a functionalized, homochiral structure over-
lapping many common motifs in target molecules. Second, it
should be either commercially available or prepared readily and
⇑
Corresponding author.
E-mail address: alampkin@samford.edu (A.J. Lampkins).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.049

J. Paige Souder et al. / Tetrahedron Letters 52 (2011) 6908–6910
6909
d
a, b, c
e
OH
H
BocHN
BocHN
BocHN
Cl
OTMS
4
BocHN
O
O
O
3a
1
2a
f
g
Boc
i
N
BocHN
I
BocHN
I
OH
O
OTMS
I
5
6
7a
h
Scheme 1. Reagents and conditions: (a) CH3I, NaHCO3, DMF; (b) NaBH4, CaCl2, THF/EtOH; (c) PyÁSO3, NEt3, CH2Cl2/DMSO, 82% (3-step); (d) SO(CH3)3I, NaH, DMSO, 60%
(d.r. = 7:1); (e) TMSCl, KCl, pyr./CH2Cl2, 20%; (f) PPh3, I2, CH2Cl2, 82%; (g) TMSCl, LiI, pyr./CH2Cl2, 87%; (h) TMSCl, imidazole, DMF, 81%; (i) 2,2-DMP, p-TsOH, MgSO4, PhCH3,
75 °C, 81%.
in the presence of pyridine. A major limitation with 6 is the acidic N–
H of the Boc group. This could preclude the use of strong bases or
nucleophiles in subsequent reaction chemistry, greatly limiting its
utility as a template or scaffold. Alternative amine protecting groups
could be screened to solve this problem, albeit at the likely expense
of adding steps to the synthesis. However, the other major problem
with 6, akin to 4, was that substitution reactions were either slug-
gish or extremely low-yielding. This was especially the case when
sterically large nucleophiles were used, suggesting the size of the
proximal i-butyl and TMS groups hinder these reactions.
R
R
Boc
R
N
BocHN
I
BocHN
O
O
OH
I
3
7
LiI, TsOH, Me2C(OMe)2, MgSO4
PhCH3, 75 oC
Scaffold 7a was prepared in good yield by warming iodohydrin
5 with 2,2-dimethoxypropane (2,2-DMP) in the presence of p-tolu-
enesulfonic acid. We believe this chiral, multifunctionalized,
orthogonally protected/reactive iodo-N,O-acetonide aminal to be
an ideal scaffold for complex molecule synthesis (Fig. 1).
We have streamlined the construction of this structurally un-
ique class of molecules by developing a novel cascade reaction to
prepare the iodo-N,O-acetonide aminal core directly from a suit-
ably functionalized epoxide (Scheme 2).6 This reaction involves
Scheme 2. Overview of the cascade reaction developed to generate iodo-
N,O-acetonide aminals (7) directly from amino acid-derived epoxides (3).
R
R
a or b
H
BocHN
2a
BocHN
O
O
, R = CHCH2(CH3)2 (Leu)
3a,
60%, dr = 7:1
2b, R = CH(CH3)2 (Val)
2c, R = CH2Ph (Phe)
the treatment of readily available
a-amino acid-derived epoxides
3b, 54% dr = 15:1
3c, 52%, dr = 10:1
(e.g., 3a–d) with lithium iodide, 2,2-dimethoxypropane, catalytic
p-TsOH, and magnesium sulfate in warm toluene to give the de-
sired iodo-N,O-acetonide aminals (7a–d) in good (59–72%) yield
(Scheme 3). This cascade reaction likely begins by protonation of
the epoxide, and subsequent nucleophilic addition of iodide. The
iodo-alcohol products of this first step (in the case of the i-butyl
series, 5) have been confirmed by independent synthesis and by
isolating small amounts from the reactions. However, this tran-
sient intermediate immediately reacts with 2,2-dimethoxypro-
pane, a reagent and cosolvent in this reaction. Condensation and
evaporation of methanol from this second step is facilitated by heat
(75 °C), and trace amounts of water are scavenged by MgSO4. The
product, iodo-aminal 7, is isolated and purified by flash chroma-
tography following standard reaction work-up.
3d,
51% dr = 10:1
2d
, R = CH2(C6H11) (Cha)
Boc
R
7a,
72%,
7b, 68%
7c,
c
N
59%
7d, 69%
O
I
Scheme 3. Reagents and conditions: (a) SO(CH3)3I, NaH, DMSO; (b) (1) Ph3PCH3I,
KHMDS, THF/DMSO, À78 °C to rt, (2) m-CPBA, CH2Cl2; (c) LiI, 2,2-DMP, p-TsOH,
MgSO4, PhCH3, 75 °C.
to other amino acids using a modular approach since the chemistry
is not vastly dependent upon the ‘R groups’ of the various residues
(except for isolated cases in which residues contain either labile or
difficult to protect ‘R groups’, for example, Arg, His, PhGly, etc.).
Scheme 3 illustrates our initial exploration into various natural
and unnatural amino acid derivatives featuring nonpolar side
chains; N-Boc protected leucine (Leu), valine (Val), phenylalanine
(Phe), and cyclohexylalanine (Cha).
We have also begun to demonstrate the scope and utility of
these scaffolds. In this vein, we have expanded this methodology
Boc
R
N
The Corey–Chaykovsky epoxidation of aldehydes 2 gave moder-
ate yields and good diastereoselectivity7 of each entry with the lone
exception of 2c. Not only were the yields of 3c consistently poor
(620%) using this epoxidation methodology, but a 1:1 mixture of
diastereomers was obtained. Thus, to generate sufficient quantities
of 3c we used a 2-step protocol involving Wittig olefination fol-
lowed by a diastereoselective epoxidation using m-CPBA.4a,8 We
O
I
7
Figure 1. The functionality contained within these iodo-N,O-acetonide aminal
scaffolds include (1) an orthogonally protected b-hydroxy amine moiety with
contiguous asymmetric centers, (2) an ‘R group’ of an amino acid, and (3) a leaving
group for substitution reactions with nucleophiles.

6910
J. Paige Souder et al. / Tetrahedron Letters 52 (2011) 6908–6910
therapeutic use in disorders of the central nervous system. The re-
sults of these investigations will be presented in due course.
Boc
Boc
a
8, X = N3 70%
N
N
9
, X = OAc 59%
10, X = SMe 64%
O
O
Acknowledgments
I
X
7a
This work was financially supported by a Research Corporation
for Science Advancement Cottrell College Science Award and
Samford University. The authors thank Dr. Mike Jablonsky (Univer-
sity of Alabama, Birmingham) and Dr. Brian Gregory (Samford Uni-
versity) for access to their respective spectroscopic equipment
facilities.
Boc
b
N
2-steps
Ref. 10
BocHN
CO2H
O
OH
CN
N-Boc-statine
11
Scheme 4. Reagents and conditions: (a) XÀ, DMSO, 50 °C; (b) KCN, DMSO, 50 °C,
69%.
Supplementary data
Supplementary data (experimental procedures and spectro-
scopic characterization data for compounds 4–6, 7a–d, and 8–11)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.10.049.
are currently investigating the precise mechanism(s) of diastereo-
facial selectivity in these epoxidation reactions computationally
and using synthetic model systems.
In all cases, epoxides 3a–d were smoothly and directly con-
verted to the desired iodo-N,O-acetonide aminals 7a–d by way of
the novel cascade process in good (59–72%) yields.9 These scaffolds
are readily soluble in organic solvents, amenable to long-term
(6–12 months) storage at À10 °C, and can be prepared on multi-
gram scale. Not unexpectedly, the 1H NMR spectra of 7 at 25 °C dis-
play the distinct N-Boc rotamers (ca. 1:1 ratio) present at this tem-
perature. Variable temperature experiments revealed those
conformationally-sensitive nuclei to cleanly coalesce at 45–50 °C.
In this vein, the corresponding carbon nuclei display extensively
broadened signals in the 13C NMR spectra, which are characteristic
of molecules containing analogous functionality.10
The reactive alkyl iodide contained within scaffolds 7a–d offers
an attractive site for a wide variety of substitution reactions under
mild conditions. Scheme 4 illustrates this utility, as scaffold 7a was
successfully treated with a variety of nucleophiles with differing
basicity and functionality. The yields of these substitution reac-
tions were good (59–70%), and each was accomplished by simply
dissolving the reagents in warm DMSO for 12 h followed by
straight-forward work-up and purification.
References and notes
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Escolano, C.; Lozano, O.; Llor, N.; Bosch, J. Org. Lett. 2003, 5, 3139–3142; (g)
Kambourakis, S.; Rozzell, J. D. Tetrahedron 2004, 60, 663–669; (h) Comins, D. L.;
King, L. S.; Smith, E. D.; Fevrier, F. C. Org. Lett. 2005, 7, 5059–5062; (i) Escolano,
C.; Amat, M.; Bosch, J. Chem. Eur. J. 2006, 12, 8198–8207; (j) Kohler, F.; Gais, H.
J.; Raabe, G. Org. Lett. 2007, 9, 1231–1234.
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Das, B. C. Eur. J. Org. Chem. 2000, 8, 1391–1399; (c) Kuethe, J. T.; Comins, D.
L. J. Org. Chem. 2004, 69, 5219–5231; (d) Arrayas, R. G.; Yin, J.; Liebeskind,
L. S. J. Am. Chem. Soc. 2007, 129, 1816–1825; (e) Coombs, T. C.; Lee, M. D.;
Wong, H.; Armstrong, M.; Cheng, B.; Chen, W.; Moretto, A. F.; Liebeskind, L.
S. J. Org. Chem. 2008, 73, 882–888.
3. (a) Marshall, J. A.; Seletsky, B. M.; Coan, P. S. J. Org. Chem. 1994, 59, 5139–5140;
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Perrone, D. Synthesis 1997, 527–529.
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1987, 52, 1487–1492; (b) Konno, H.; Toshiro, E.; Hinoda, N. Synthesis 2003, 14,
2161–2164.
5. Stamatov, S. D.; Stawinski, J. Eur. J. Org. Chem. 2008, 2635–2643.
6. For recent examples of using epoxides in cascade reactions, see: (a) Yadav, J. S.;
Reddy, B. V. S.; Reddy, G. M.; Chary, D. N. Tetrahedron Lett. 2007, 48, 8773–8776; (b)
Volkova, Y. A.; Ivanova, O. A.; Budynina, E. M.; Averina, E. B.; Kuznetsova, T. S.;
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We envision widespread application for functionalized chiral
templates of this nature (7–11), most notably for rapid/efficient ac-
cess to highly sought after peptide-derived natural products and/or
biologically relevant molecules. For instance, this technology af-
fords expedited access to nitrile 11, which Yuste and co-workers10
used to prepare the N-Boc protected form of statine, a b-hydroxy-
7. Ratios were determined by 1H NMR analysis of the crude reaction mixture and
verified by isolation of the individual diastereomers by column
chromatography.
8. Smith, A. B., III; Benowitz, A. B.; Sprengeler, P. A.; Barbosa, J.; Guzman, M. C.;
Hirschmann, R.; Schweiger, E. J.; Bolin, D. R.; Nagy, Z.; Campbell, R. M.; Cox, D.
C.; Olson, G. L. J. J. Am. Chem. Soc. 1999, 121, 9286–9298.
c-amino acid widely used as a linchpin component of peptidomi-
metic aspartic protease inhibitors. Further, the azide group within
8 represents a synthetic handle for ‘click’ chemistry with terminal
acetylenes. This methodology has found widespread use as a bio-
conjugation strategy due to its high yields, functional group toler-
ance, and robust 1,2,3-triazole products.
In summary, we present a family of amino acid-derived iodo-
N,O-acetonide aminal synthetic scaffolds containing non-epimeriz-
able contiguous asymmetric centers and introduce a novel epoxide
opening/cyclization cascade reaction to efficiently prepare them.
These platforms are attractive substrates for complex molecule
synthesis due to their orthogonal protection motif, inherent chiral-
ity, and ability to directly undergo substitution chemistry with an
array of nucleophiles. We are currently expanding this methodol-
ogy to various other amino acid derivatives and utilizing these
scaffolds to construct biologically active peptide-derived natural
9. Representative procedure for the cascade reaction of epoxides
3 to iodo-
N,O-acetonide aminals 7. To a solution of 3b (0.100 g, 0.465 mmol) in dry
toluene (5 mL) was added LiI (0.156 g, 1.16 mmol), TsOHÁH2O (0.035 g,
0.186 mmol), 2,2-dimethoxypropane (2.8 mL), and anhydrous MgSO4 (0.279 g,
2.33 mmol) was added. The reaction was heated to 75 °C and allowed to stir for
6 h. The reaction was then allowed to cool to room temperature and filtered. The
filtrate was evaporated, and the residue dissolved in methylene chloride and
washed with saturated aqueous sodium bicarbonate, water, and brine. The
solution was then dried with magnesium sulfate and filtered. The crude product
was purified via column chromatography (12:1 hexanes:EtOAc) to afford 7b
(121 mg, 68%) as a colorless solid. [
a]
D À4.1 (c 1.1, CH2Cl2). 1H NMR (700 MHz,
CDCl3) d 0.96 (d, J = 6.7 Hz, 6H), 1.48 (s, 9H), 1.52 (s, 3H), 1.64 (s, 3H), 2.07 (br, 1H),
3.25 (d, J = 5.9 Hz, 2H), 3.81 (br, 1H), 4.11 (m, J = 6.6 Hz, 1H). 13C NMR (175 MHz,
50 °C, CDCl3) d 9.8, 18.4, 19.2, 27.8, 28.4, 30.0, 31.5, 67.1, 77.8, 80.1, 94.6, 152.3.
MS (ESI) for C14H26INO3 (M+Na)+ 406.09, found 406.13.
10. Yuste, F.; Diaz, A.; Ortiz, B.; Sanchez-Obregon, R.; Walls, F.; Garcia Ruano, J. L.
Tetrahedron: Asymmetry 2003, 14, 549–554.
products and lipophilic non-natural b-, and
c-peptides for